Glucocorticoid-induced TNFR-related gene (GITR:TNFRSF18), sometimes also referred to as Activation-Inducible TNFR family member (AITR), is a receptor belonging to the TNF receptor superfamily (TNFRSF). It is activated by its cognate ligand, GITR ligand (GITRL, TNFSF18). GITR is a type I transmembrane protein that contains a cysteine-rich extracellular domain, which is characteristic of TNFR family members. The cytoplasmic domain of GITR, for instance, shares close homology with certain other TNFR family members, such as 4-1BB and CD27 (Nocentini, et al. (1997) Proc. Natl. Acad. Sci. 94:6216-6221).
Human GITR is expressed at low levels in responder resting T cells, with CD4+ cells exhibiting increased expression relative to CD8+ cells. GITR expression is up-regulated significantly for several days following T cell activation. GITR is constitutively expressed at high levels in regulatory T cells (Tregs), such as CD4+CD25+ or CD8+CD25+ cells, and is further up-regulated when these cells are activated (Nocentini and Riccardi (2005) E. J. Immunol. 35:1016-1022). GITR expression is not exclusively limited to T cells, however. Reports have also indicated that GITR is expressed on NK cells, macrophages, B cells, dendritic cells, mast cells and monocytes (Nocentini and Riccardi (2005) E. J. Immunol. 35:1016-1022).
GITRL is a type II transmembrane protein as is typical for most TNF ligand family members. Current research indicates that human GITRL typically exists as a trimer, although it can also be present as a monomer or assemble into other multimeric forms (Chattopadhyay, et al. (2007) Proc. Natl. Acad. Sci. 104:19452-19457; Zhou, et al. (2008) Proc. Natl. Acad. Sci. 105:635-640). There is some evidence suggesting that a soluble form of GITRL is also produced (Baltz, et al. (2008) Blood 112:3735-3743; Mahesh, et al. (2006) Eur. J. Immunol. 36: 2128-2138). GITRL is expressed primarily on antigen presenting cells (APC), including macrophages, B cells, dendritic cells and endothelial cells that can function as APC (Nocentini and Riccardi (2005) E. J. Immunol. 35:1016-1022; Agostini, et al. (2005) Infect. Immun. 73:7502-7508; and Nocentini, et al. (2007) E. J. Immunol. 37:1165-1169).
Binding of GITRL on APC to GITR on responder T cells triggers GITR signaling, which co-stimulates responder T cells and inhibits the suppressive activity of Treg cells. GITR signaling functions as a co-activating signal to both CD4+ and CD8+naïve T cells, thereby inducing or enhancing proliferation and effector function, particularly when T cell receptor (TCR) stimulation is suboptimal (Schaer, et al. (2012) Curr. Opin. Immunol. 24:217-224). More specifically, GITR can have several effects on effector T cells and regulatory T cells, including: co-stimulation and activation of effector T cells such that they are more resistant to inhibition, inhibiting regulatory T cells, decreasing the sensitivity of effector T cells to suppression by regulatory T cells and partial deletion of regulatory T cells in the circulation (Nocentini, et al. (2007) Eur. J. Immunol. 37:1165-1169).
Collectively, the foregoing activities, in particular the costimualtion of responder T cells and abrogation of the suppressor activity of regulatory T cells, means that GITR activation results in an enhanced immune response. Such activation has the potential to restore immune responses to infections and to tumors. Accordingly, molecules capable of activating GITR would be of value as immunostimulatory agents in settings in which it is desirable to trigger an enhanced immune response.